When Shakespeare warned, in the Merchant of Venice, that "the sins of the father are to be laid upon the children," he might have been referring to metabolism-related epigenetic editing. Rapid weight gain after birth is an established risk factor for the development of heart disease, metabolic syndrome, and diabetes later in life. Furthermore, overnutrition early in life, especially in males, has been associated with an increased risk of cardiometabolic diseases in subsequent generations. These findings imply the existence of a sex-specific transgenerational inheritance pattern of metabolic programming. However, the lack of appropriate animal models of neonatal overnutrition and its transgenerational effects has limited our understanding of this phenomenon in humans.

Pentinat et al. use a novel mouse model of neonatal overnutrition and accelerated growth to demonstrate that excessive weight gain in males during sensitive periods of development in early life has adverse metabolic consequences both for the affected animal and for subsequent generations of offspring. In their study, the authors induced neonatal overgrowth (ON-F0) by culling offspring to four pups per dam during lactation (versus eight pups per dam in the control group). By age 4 months, ON-F0 male mice manifested many features of the metabolic syndrome (such as obesity, insulin resistance, and glucose intolerance), whereas the control mice did not. In subsequent rounds of experiments, the male offspring (ON-F1) and grand-offspring (ON-F2) of the ON-F0 male mice were not overfed during lactation but still developed features of the metabolic syndrome by 4 months of age. Specifically, the male ON-F1 offspring developed fed and fasting hyperinsulinemia, hypertriglyceridemia, insulin resistance, and glucose intolerance, whereas the male ON-F2 mice developed a more modest phenotype of fasting hyperglycemia and glucose intolerance.

These new observations of transgenerational inheritance of metabolic dysfunction through the paternal lineage and the progressive weakening of phenotypes through subsequent generations suggest that metabolic programming is influenced by nutritionally induced epigenetic modifications of the gamete genomes. Given the prevalence of overweight male infants in today’s society, these findings have serious implications for the health of future generations and reinforce the importance of preventative efforts directed at childhood obesity.